Discovery and Design of Tricyclic Scaffolds as Protein Kinase CK2 (CK2) Inhibitors through a Combination of Shape-Based Virtual Screening and Structure-Based Molecular Modification

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• 作者：Haopeng Sun ; Xiaoli Xu ; Xiaowen Wu ; Xiaojin Zhang ; Fang Liu ; Jianmin Jia ; Xiaoke Guo ; Jingjie Huang ; Zhengyu Jiang ; Taotao Feng ; Hongxi Chu ; You Zhou ; Shenglie Zhang ; Zongliang Liu ; Qidong You
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2013
• 出版时间：August 26, 2013
• 年：2013
• 卷：53
• 期：8
• 页码：2093-2102
• 全文大小：524K
• 年卷期：v.53,no.8(August 26, 2013)
• ISSN：1549-960X

文摘

Protein kinase CK2 (CK2), a ubiquitous serine/threonine protein kinase for hundreds of endogenous substrates, serves as an attractive anticancer target. One of its most potent inhibitors, CX-4945, has entered a phase I clinical trial. Herein we present an integrated workflow combining shape-based virtual screening for the identification of novel CK2 inhibitors. A shape-based model derived from CX-4945 was built, and the subsequent virtual screening led to the identification of several novel scaffolds with high shape similarity to that of CX-4945. Among them two tricyclic scaffolds named [1,2,4]triazolo[4,3-c]quinazolin and [1,2,4]triazolo[4,3-a]quinoxalin attracted us the most. Combining strictly chemical similarity analysis, a second-round shape-based screening was performed based on the two tricyclic scaffolds, leading to 28 derivatives. These compounds not only targeted CK2 with potent and dose-dependent activities but also showed acceptable antiproliferative effects against a series of cancer cell lines. Our workflow supplies a high efficient strategy in the identification of novel CK2 inhibitors. Compounds reported here can serve as ideal leads for further modifications.